The HIV/AIDS pandemic inflicts approximately 40 million people worldwide. The persistence of HIV in anatomic sanctuary sites such as the brain prevents viral eradication. One of the major natural reservoirs of HIV is macrophages, in particular infected-macrophages infiltrated into the brain also cause neuronal injury. Although the antiretroviral therapy (ART) inhibits viral replication, it does not selectively eliminate vira reservoirs. As such, with the greater life expectancy of infected people, the prevalence of HIV-associated neurological disorder has become a prominent problem. In this proposal, we plan to test a new therapeutic strategy to selectively target viral production and reactivation in the brai in SIV/rhesus macaque model. We have developed a novel HIV/SIV Rev-dependent lentiviral vector carrying therapeutic genes to target HIV/SIV infection. Using this system, we have demonstrated selective killing of HIV-positive cells in cell culture conditions. The proposed research is the first attempt to apply this novel technology to reduce viral persistence in the brain of SIV-infected animals. We plan to test a therapeutic gene, the herpes virus thymidine kinase (HSV1- tk), in rhesus macaques. The Rev-mediated expression of HSV1-tk has the potential to be practically used for the treatment of HIV infection, and may eventually lead to a solution to the disease.